Lecture 2

Question 1

What is the major tissue of elimination?

Answer 1

Kidneys

Question 2

How much blood goes to the kidneys?

Answer 2

1/4

Question 3

Tissue of elimination, not kidneys?

Answer 3

Enterohepatic Circulation

Question 4

Other tissues of elimination

Answer 4

Sweat/saliva/lacrimation (rifampin); certain drugs contraindicated if wear contacts
Pulmonary: volatile anesthetics, EtOH
Mammary tissue: via lactation

Question 5

Renal Clearance

Answer 5

ml/min
rate of renal excretion (mg/min)/
plasma concentration (mg/ml)

Question 6

Chronic HTN associated with DM destroys the glomerular capillaries. This could mean:

Answer 6

Elevated Cmax &
Extend (lengthen) half-life &
Shorten onset time of drug

Question 7

Why do reductions in renal blood flow and GFR increase drug toxicity?

Answer 7

Increases Cmax and half-life

Question 8

Plasma Binding Proteins (PBP)

What are they? Which is the most common?

Answer 8

Reversibly bind drugs in blood stream, inactivating them because too big to leave blood vessel. Main PBP is albumin.

Question 9

What are 2 main PBP

Answer 9

Albumin, which has a low affinity (so drug needs to be in high concentrations), is least selective, is most common
Globulin, which has high affinity (so will bind drugs in low concentrations), selective binding to sex steroids.

Question 10

How is PBP a reservoir?

Answer 10

Drugs are bound reversibly, so when free concentration drops, can unbind from PBP. While bound, not metabolized or excreted.

Question 11

How is PBP effected by disease states in liver, kidneys, diet?

Answer 11

Malnourishment, liver (hepatic disease decreases PBP) and kidney disease (proteinuria) cause decreased amounts of PBP, so many meds have greater free concentration which increases toxicity.

Question 12

What effect does tissue deposits have?

Answer 12

1. Serve as a reservoir for a drug.
2. Alter dosing strategies. (loading/induction/priming) and maintenance.
3. sites of toxicity

Question 13

Where does most metabolism occur and by what?

Answer 13

Liver by P450 system.

Most drugs are metabolized by 3 families of CYP enzymes, CYP1, CYP2, CYP3

Question 14

What 3 things affect metabolism?

Answer 14

1. Age (old and young)
2. inducers: increase metabolism by increasing CYP synthesis
3. Inhibitors: Decrease metabolism by interfering with CYP synthesis.

Question 15

What are the major metabolic tissues?

Answer 15

Liver, kidneys, GI tract, lungs, blood plasma

Question 16

Where are CYPs in liver?

Answer 16

In ER

Question 17

3 classes of Metabolic Enzymes

Answer 17

1. Microsomal (CYPs)
2. Hydrolytic (eg: pseudocholinesterase)
3. Conjugation: glutathione S transferase

Question 18

How do CYP enzyme inducers work?

Answer 18

the xenobiotic(drug inducer)==>orphan receptor==>CYP gene==>increases production of CYP enzyme (induction)==>increases metabolism==>decreases xenobiotic==>decreases orphan receptor stimulation and therefore CYP gene activation.

Question 19

Conjugation Enzymes

Answer 19

Enzymes that conjugate a conjugation molecule (like glutathione) to a drug. The complex is inactivated and has increased water solubility, increasing its renal excretion.

Question 20

Metabolic Phases

Answer 20

1. CYP or hydrolysis

2. Conjugation

Question 21

First Pass Metabolism

Answer 21

Where most of an oral drug is metabolized before reaching circulation.
GI tract_hepatic portal vein_liver_IVC_systemic circulation

Question 22

Biotransformation

Answer 22

An act of metabolism

1. drug inactivation
2. Prodrug activation

Question 23

Metabolism in drug resistance

Answer 23

Some cancer cells increase production of conjugation enzymes to kill anticancer drugs (increase glutathione S-transferase)

Question 24

Individualized factors

Answer 24

Males metabolize benzos faster

Question 25

What does our microbiota have to do with metabolism?

Answer 25

There are 100x more genes in our microbiome.

These genes affect our absorption and metabolism, like in digoxin, acetaminophen, tamoxifen, simvastatin.

Question 26

Major tissues of elimination:

Answer 26

1. Renal
2. EHC (enterohepatic circulation)
3. Sweat/Lacrimation/saliva
4. Pulmonary
5. Mammary

Question 27

EHC

Answer 27

Drug in GI tract_hepatoportal vein_Liver_drug+bile salts_bile_small intestine_blood plasma or feces. This process occurs many times before drug is completely eliminated in feces.

Question 28

What is the effect of multiple drugs in regards to PBP?

Answer 28

Sometimes drugs will compete for binding sites and one drug can end up with higher free fraction, causing increased intensity of response or toxicity.